Osteoporosis is a major public health issue caused by a reduction in bone mineral density in mature bone and results in fractures after minimal trauma. The most common fractures occur in the vertebrae, distal radius (Colles' fracture) and hip. An estimated one-third of the female population over age 65 will have vertebral fractures, caused in part by osteoporosis. Moreover, hip fractures are likely to occur in about one in every three woman and one in every six men by extreme old age.
Two distinct phases of bone loss have been identified. One is a slow, age-related process that occurs in both genders and begins at about age 35. This phase has a similar rate in both genders and results in losses of similar amounts of cortical and cancellous bone. Cortical bone predominates in the appendicular skeleton while cancellous bone is concentrated in the axial skeleton, particularly the vertebrae, as well as in the ends of long bones. Osteoporosis caused by age-related bone loss is known as Type II osteoporosis.
The other type of bone loss is accelerated, seen in postmenopausal women and is caused by estrogen deficiency. This phase results in a disproportionate loss of cancellous bone, particularly trabecular bone. Osteoporosis due to estrogen depletion is known as Type I osteoporosis. The main clinical manifestations of Type I osteoporosis are vertebral, hip and Colles' fractures. The skeletal sites of these manifestations both contain large amounts of trabecular bone. Bone turnover is usually high in Type I osteoporosis. Bone resorption is increased but there is inadequate compensatory bone formation. Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemotherapy, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression, and oophorectomy.
The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) that then refill with new bone the cavity left by the osteoclasts.
In a healthy adult subject, osteoclasts and osteoblasts function so that bone formation and bone resorption are in balance. However, in osteoporotics an imbalance in the bone remodeling process develops which results in bone being replaced at a slower rate than it is being lost. Although this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in postmenopausal osteoporotics, following oophorectomy, or in iatrogenic situations such as those resulting from the use of corticosteroids or immunosuppressors.
The diagnosis and management of bone related disease, such as osteoporosis, typically requires information about bone turnover and bone mass. Determinations of bone turnover have historically been performed utilizing standard serum, urine and/or sweat laboratory tests including fasting calcium/creatinine, hydroxyproline, alkaline phosphatase and/or osteocalcin/bone growth protein utilizing standard high pressure liquid chromatography (HPLC) techniques. To illustrate, whenever bone formation occurs (calcium deposition) or bone resorption occurs (calcium breakdown), various chemical reactions occur within the body that elevate the presence of certain indicators in the blood and urine suggesting changes in the calcium/bone mineral status. Biomarkers, however, typically lack information on the severity or stage of a disease and, additionally, on the morphological condition of an organ or tissue.
Recently, several new bone specific assays have been developed which enable bone turnover to be evaluated with an ELISA/EMIT immunoassay format. Descriptions of these immunoassay formats can be found in U.S. Pat. Nos. 5,973,666, 5,320,970, 5,300,434 and 5,140,103. The labeling for the new assays utilize a biochemical marker to quantify bone resorption and/or formation and provides information on bone turnover.
For diagnosis of bone diseases, U.S. Pat. No. 6,210,902 describes detecting collagen breakdown products in serum or urine by using two or more immunoassays, and forming a ratio between the concentration of one fragment and a second fragment to form an index to determine the rate of bone resorption. In another method of forming an index of biomarker results, U.S. Pat. No. 5,962,236 obtains a ratio of free lysyl pyridinoline cross-links and creatinine content to form a urinary index of bone resorption to diagnose bone disease. Further, the use of two or more biomarkers to diagnose a disease, where a neural network is first trained and the trained neural network is then used to analyze the experimental data to produce a diagnostic value is disclosed in U.S. Pat. Nos. 6,306,087 and 6,248,063.
Bone mass determinations, on the other hand, have been traditionally performed by using various x-ray based techniques including single and dual-photon absorptiometry (SPA and DPA), quantitative computed tomography (QCT), and dual-energy absorptiometry (DXA). Imaging tests such as x-rays, ultrasound, computed tomography and MRI can provide detailed information about the morphological condition of an organ or a tissue and on the severity or the stage of a disease process. However, such imaging techniques typically lack information on the metabolic activity of various tissues and organs and, in diseased states, cannot give an estimate of the rate of progression or the prognosis of a disease.
U.S. Pat. No. 5,785,041 describes a computer system for displaying biochemical data with data from densitometric bone measurement to determine whether bone formation or bone resorption is occurring.
Thus, there remains a need for methods and devices for diagnosing, prognosticating and monitoring of osteoporosis by combining the information provided by imaging tests with the information provided by biomarkers.